Histamines are representative chemical mediators that induce allergic reactions, and the histamines are released from cells such as mast cells and basocytes when substances that are causative of allergy are entered into the body. The released histamines are bound to a histamine type 1 receptor (H1 receptor) protein to exhibit pharmacological actions such as hypotension, vascular hyperpermeability, constriction of smooth muscles, vasodilatation, or glandular hypersecretion, and involved in the manifestation of allergic reactions and inflammations. As described above, histamines are related to various diseases of human, and the allergic diseases and inflammations can be prevented or cured by controlling their actions. Agents for controlling histamine release and agents for inhibiting the binding of histamines with receptors (antihistamines) are numerously commercially available, and the agents are used in diseases such as bronchial asthma, allergic rhinitis, pollinosis, urticaria, and atopic dermatitis.
However, antihistamines that are conventionally known exhibit some undesired side effects such as sedative action, drowsiness, dizziness, and malaise, based on the actions on the central nervous system; and dry mouth, mucosal dryness, and visual impairment, based on the anti-cholinergic actions; therefore, there are some limitations of use such as prohibition of taking histamines before driving automobiles, which in turn cause inconvenience in use. For these reasons, antihistamines which are free from such problems and have excellent effects are in demand from the patients and the medicinal sites.
In view of the above, as a result of intensive studies, the present inventors have found the oxepin derivative of the present invention having smaller side effects of the central nervous system and potent antihistamine action. The oxepin derivatives have been known to have anti-asthmatic action (see Patent Publication 1); dopamine antagonistic action (see Patent Publication 2); δ-opioid regulatory action (see Patent Publication 3); and the like; however, the derivatives that have smaller side effects in the central nervous system such as drowsiness, and potent antihistamine actions, as in the compounds of the present invention, have not been known.
Patent Publication 1: Japanese Patent Laid-Open No. Sho 56-150082
Patent Publication 2: Japanese Patent Laid-Open No. Sho 58-188879
Patent Publication 3: WO 2005/003131